S100A7 induction is repressed by YAP via the Hippo pathway in A431 cells

Abstract

YAP is an oncogenic transcriptional co-activator and is inhibited by the Hippo pathway. Recent studies have revealed that YAP is also a sensor of cell morphology and cell density and can be phosphorylated by cytoskeleton reorganization. Our previous study demonstrated that S100A7 was upregulated in several squamous cell carcinoma (SCC) specimens and was dramatically induced in SCC cells by suspension and dense culture as well as in xenografts. However, little is known about how S100A7 induction occurs in cancer cells. Here, we identify that S100A7 induction is accompanied by YAP phosphorylation in both suspended and dense A431 cells. This correlation reverses after recovery of cell attachment or relief from dense culture. Further examination finds that S100A7 induction is repressed by nuclear YAP, which is further validated by activation or inhibition of the Hippo pathway via loss- and/or gain-of- LATS1 and MST1 function. Strikingly, disruption of the F-actin promotes S100A7 expression via YAP by activation of the Hippo pathway. Furthermore, we demonstrate that repression of S100A7 by YAP required TEAD1 transcriptional factor. Taken together, our findings demonstrate for the first time that S100A7 is repressed by YAP via the Hippo pathway.

YAP Expression and Activity Are Suppressed by S100A7 via p65/NFκB-mediated Repression of ΔNp63

“…Interestingly, our previous study uncovered that S100A7 induction was also repressed by YAP through activation of the Hippo pathway in A431, HCC94, and FaDu cells under suspend and dense culture or F-actin disruption (8,9). Combined with the findings in this study, we conclude that there is a negative correlation of S100A7 and YAP, and reciprocal negative regulation between the two proteins in SCC cells, at least in A431, HCC94, and FaDu cells.…”

“…Although S100A7 expression is negatively regulated by nuclear YAP, both S100A7 and YAP perform the similar functions in promoting cells' proliferation and inhibiting squamous differentiation (8)(9)(10). In this report, we provide evidence that S100A7 also inhibits YAP expression and activity through p65/NFkBmediated repression of DNp63, and S100A7 represses druginduced apoptosis via inhibition of YAP.…”

“…First, overexpression of S100A7 in A431 cells promoted cell proliferation and inhibited differentiation, whereas the opposite results were obtained in silencing of S100A7 in HCC94 cells (11). Similarly, knockdown of YAP in all these three cells resulted in a decrease in the growth of cells (8,9). Second, either inhibition or activation of chemotherapy-induced apoptosis was observed in S100A7-overexpressed cells or S100A7-silenced cells, suggesting that S100A7 expression reduced the chemosensitivity in these cells.…”

“…In addition, increased S100A7 expression has been reported in nearly all types of SCC tissues as well as adenocarcinomas of the breast (3)(4)(5)(6)(7). Our recent works uncovered that the S100A7 acted as a dual regulator in promoting proliferation and suppressing differentiation in several SCC cells (8)(9)(10)(11). S100A7 has also been shown to be attributed to resistance of anoikis resulting in tumor growth by activating several signaling pathways (12,13).…”

“…S100A7 has also been shown to be attributed to resistance of anoikis resulting in tumor growth by activating several signaling pathways (12,13). Interestingly, S100A7 has been induced by cytokines, cell dense and suspension culture, and by activation of the Hippo pathway (8,9).…”